Learning disorders, attention deficits, aggressive and disruptive behaviors are long-term consequences of early lead exposure. Other adverse effects include cortical gray matter volume loss and functional deficits with evidence of brain reorganization. There is a critical need to understand the mechanisms of lead-induced neurotoxicity. The long-term goal of this research is to identify the mechanisms behind the delayed behavioral effects of lead exposure and to treat or prevent those behaviors. The objective of the studies outlined in this R21 proposal is to determine whether an association exists between lead exposure and epigenetic, DNA methylation patterns in the brain. The central hypothesis for this study is that prenatal and early postnatal exposure to lead causes brain injuries that are associated with permanent modifications of the individual epigenome in the injured regions and that these modifications cause alterations of DNA methylation and subsequent changes in global gene expression profiles. The rationale for this project is that knowing what epigenetic changes result from lead exposure and how they are associated with brain abnormalities will shed light on the mechanisms of lead toxicity, as well as suggest possible preventative strategies. The following specific aims will be completed: 1) determine brain regions most affected by lead exposure in mice and 2) conduct comparative analyses of DNA methylation and gene expression in the areas of brain affected by lead exposure. These aims test the working hypothesis that lead exposure results in brain abnormalities that are detectable with imaging and that epigenetic alterations occur in the affected brain regions. To achieve these aims, mice exposed to varying doses of lead during gestation and early life will be imaged and brain volumes, white matter integrity, and neurochemistry will be quantified and correlated with blood lead levels. In those regions showing an effect of lead exposure, global DNA methylation and gene expression patterns that differ from the corresponding areas in unexposed mice will be identified. The expected contribution is a better understanding of the fundamental mechanism(s) of the delayed manifestations of lead neurotoxicity. This contribution will be significant because it will provide direct evidence of the causal link between lead exposure and developmental brain changes that could explain the delayed behavioral effects of such exposure. Once this information is available, prevention and intervention through pharmacologic, dietary and trophic factors will be possible. This work is innovative because it combines advanced neuroimaging studies of lead intoxication in an animal model with epigenetic studies to better understand the long-term consequences of lead exposure. The expected outcome of this work is the establishment of a link between brain injury and epigenetic changes, which lays the foundation for determining how these epigenetic changes influence behavior later in life. PUBLIC HEALTH RELEVANCE: Lead contamination is a world-wide environmental problem and studies on the health effects of low-level environmental lead exposure are urgently needed. Conservative estimates put the cost of lead poisoning in children and the associated neurobehavioral disorders caused by it at around 2.8% ($52.6 billion) of the total health care costs of the US. To study plausible causes of lead morbidity, the current application will characterize global epigenomics patterns in the brain of mice experimentally exposed to lead.